The proposed R34 Exploratory Clinical Research Grant is designed in response to Program Announcement PAR-10-005, to determine the feasibility of conducting a Phase III randomized clinical trial comparing two doses of recombinant factor VIII (r.FVIII) prophylaxis in adults with severe hemophilia A. This will be accomplished by 1) conducting a pilot clinical trial at six core hemophilia treatment centers (HTCs), the Directors of which participated in initial design and planning of this concept through participation in the NHLBI State of the Science (SoS) Hemophilia and Von Willebrand Disease Subcommittee; and 2) setting up an infrastructure of 47+ HTC physicians to reach consensus on study design, subject recruitment, and study participation, and operationalizing the infrastructure to accomplish centralized IRB and contract submission and adequate enrollment. A major goal of comprehensive hemophilia care is to prevent occurrence of bleeds by prophylaxis, or regular preventive factor three times weekly. Although prophylaxis is effective in reducing bleeding and joint damage in children, whether it is necessary to continue into adulthood is not known. We hypothesize that adults with mature cartilage and joints are less susceptible to joint bleeds and joint damage, and that once weekly r.FVIII prophylaxis, with up to two rescue doses per week, is as effective as thrice-weekly prophylaxis in reducing bleeding frequency, but less costly and more acceptable with higher quality-of-life. The ultimate goal of this project is to identify and resolve barriers to the conduct of a future phase III randomized, controlled clinical trial of prophylaxis in adults with hemophilia. By this approach, we hope to prepare, refine, and optimize methods, forms, and operating procedures; and assure a sufficient number of participating sites and eligible available subjects, in order to assure the feasibility of conducting a Phase III randomized controlled trial of prophylaxis in adults with severe hemophilia A, the specific aims of which are: Aim 1. To determine the feasibility of a phase III randomized, non-inferiority, cross-over clinical trial of adult prophylaxis in severe hemophilia A by conducting a pilot trial in 20 adult men with severe hemophilia A, F.VIII <0.01 U/ml, and age > 18 years. The study will be conducted in six core HTCs and designed to compare once-weekly vs. thrice-weekly rF.VIII for 52 weeks. The primary efficacy endpoint will be joint bleeding frequency. Joint range of motion, factor usage, cost, quality-of-life, and inter-dose hypocoagulability by thrombin generation time and F.VIII activity will also be determined. Safety will be measured by the frequency of bleeding unresponsive to up to two rescue treatments. Safety will be measured by the frequency of bleeding unresponsive to up to two rescue treatments. Subject acceptance and adherence to the treatment interventions will be determined; web-based case report forms, digital imaging for joint range of motion, quality-of-life forms will be assessed; and blood sample collection and shipping optimized. Aim 2. To establish an HTC infrastructure of 47+ HTC physicians through facilitated focus groups and in- person meetings to jointly build consensus on trial design, subject recruitment, and trial participation to assure a sufficient number of eligible subjects to conduct a future R01 52-week randomized cross-over trial. The HTC infrastructure will be operationalized by hiring a dedicated nurse coordinator to prepare IRB submission and contracts for participating HTCs. The six core HTC physicians will review and finalize case report forms and the manual of operations for the future R01 trial, and exploratory meetings will be held with foreign HTC physicians to determine the potential for study participation and subject recruitment to assure the feasibility of conducting a future Phase III randomized clinical trial.